Genetic Variant KNG1:c.*757T>C (chr3-186743088-T-C) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_001102416.3(KNG1):c.*757T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.42 in 325,314 control chromosomes in the GnomAD database, including 29,240 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.43 ( 14048 hom., cov: 31)

Exomes 𝑓: 0.41 ( 15192 hom. )

Consequence

KNG1
NM_001102416.3 3_prime_UTR

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.343

Publications

10 publications found

Variant links:

Genes affected

KNG1 (HGNC:6383): (kininogen 1) This gene uses alternative splicing to generate two different proteins- high molecular weight kininogen (HMWK) and low molecular weight kininogen (LMWK). HMWK is essential for blood coagulation and assembly of the kallikrein-kinin system. Also, bradykinin, a peptide causing numerous physiological effects, is released from HMWK. Bradykinin also functions as an antimicrobial peptide with antibacterial and antifungal activity. In contrast to HMWK, LMWK is not involved in blood coagulation. Infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) reduces or depletes angiotensin converting enzyme 2 (ACE2), which results in an increase in levels of des-Arg(9)-bradykinin, a bioactive metabolite of bradykinin that is associated with lung injury and inflammation. Three transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Sep 2020]

KNG1 links:

HRG-AS1 (HGNC:55915): (HRG and FETUB antisense RNA 1)

HRG-AS1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.81).

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.609 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein
KNG1	NM_001102416.3 link	c.*757T>C	3_prime_UTR_variant	Exon 10 of 10	ENST00000644859.2	NP_001095886.1
KNG1	NM_000893.4 link	c.1204-617T>C	intron_variant	Intron 10 of 10		NP_000884.1
KNG1	NM_001166451.2 link	c.1096-617T>C	intron_variant	Intron 9 of 9		NP_001159923.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KNG1	ENST00000644859.2 link	c.*757T>C		3_prime_UTR_variant	Exon 10 of 10		NM_001102416.3	ENSP00000493985.1

Frequencies

GnomAD3 genomes

AF:

0.426

AC:

64680

AN:

151790

Hom.:

14031

Cov.:

show subpopulations

Gnomad AFR

AF:

0.430

Gnomad AMI

AF:

0.566

Gnomad AMR

AF:

0.361

Gnomad ASJ

AF:

0.437

Gnomad EAS

AF:

0.405

Gnomad SAS

AF:

0.629

Gnomad FIN

AF:

0.432

Gnomad MID

AF:

0.408

Gnomad NFE

AF:

0.422

Gnomad OTH

AF:

0.426

GnomAD4 exome

AF:

0.414

AC:

71836

AN:

173406

Hom.:

15192

Cov.:

AF XY:

0.417

AC XY:

34644

AN XY:

83170

show subpopulations

African (AFR)

AF:

0.425

AC:

1356

AN:

3188

American (AMR)

AF:

0.362

AC:

AN:

254

Ashkenazi Jewish (ASJ)

AF:

0.458

AC:

506

AN:

1106

East Asian (EAS)

AF:

0.394

AC:

292

AN:

742

South Asian (SAS)

AF:

0.634

AC:

2162

AN:

3408

European-Finnish (FIN)

AF:

0.382

AC:

AN:

Middle Eastern (MID)

AF:

0.459

AC:

156

AN:

340

European-Non Finnish (NFE)

AF:

0.408

AC:

64895

AN:

158864

Other (OTH)

AF:

0.432

AC:

2364

AN:

5470

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

2121

4242

6364

8485

10606

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2714

5428

8142

10856

13570

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.426

AC:

64726

AN:

151908

Hom.:

14048

Cov.:

AF XY:

0.427

AC XY:

31697

AN XY:

74222

show subpopulations

African (AFR)

AF:

0.430

AC:

17811

AN:

41408

American (AMR)

AF:

0.361

AC:

5502

AN:

15248

Ashkenazi Jewish (ASJ)

AF:

0.437

AC:

1518

AN:

3470

East Asian (EAS)

AF:

0.405

AC:

2092

AN:

5166

South Asian (SAS)

AF:

0.628

AC:

3022

AN:

4812

European-Finnish (FIN)

AF:

0.432

AC:

4550

AN:

10524

Middle Eastern (MID)

AF:

0.405

AC:

119

AN:

294

European-Non Finnish (NFE)

AF:

0.422

AC:

28693

AN:

67960

Other (OTH)

AF:

0.427

AC:

904

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1872

3744

5616

7488

9360

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

606

1212

1818

2424

3030

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.422

Hom.:

18507

Bravo

AF:

0.416

Asia WGS

AF:

0.512

AC:

1784

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.81

CADD

Benign

6.9

(source)

DANN

Benign

0.74

PhyloP100

0.34

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over